picibanil and Mouth-Neoplasms

The cellular immunity of peripheral blood was analyzed to evaluate the efficacy of OK-432 between 3 groups of patients with oromaxillary squamous cell cancer, which were composed of 14 patients in the pretreatment stage, 8 patients who were free from cancer more than one year after the last cancer therapy and had been continuously treated with OK-432, and 14 patients who had undertaken cancer therapy without OK-432 and were also free from cancer for at least one year. As parameters of cellular immunity, leucocyte counts, percent composition of T-cells, percent compositions of T-lymphocyte subsets (OKIal+, OKT3+, OKT4+, and OKT8+) and the ratio of OKT4+ and OKT8+, PPD skin test, and lymphocytic blastogenesis induced by PHA and Con-A, were examined. The results showed no significant difference between the patients treated with and without OK-432. Nor was there any significant difference between the pretreatment group and the posttreatment groups with and without OK-432 treatments in any of the examined immunologic parameters.

Topics: Adult; Aged; Carcinoma, Squamous Cell; CD4-Positive T-Lymphocytes; Female; Humans; Immunity, Cellular; Immunotherapy; Jaw Neoplasms; Leukocyte Count; Lymphocyte Activation; Male; Middle Aged; Mouth Neoplasms; Picibanil; T-Lymphocytes, Regulatory

Topics: Administration, Oral; Adolescent; Adult; Aged; Antineoplastic Agents; Carcinoma, Adenoid Cystic; Carcinoma, Squamous Cell; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Mouth Neoplasms; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Picibanil; Proteoglycans; Tegafur

Topics: Adult; Diagnosis, Differential; Follow-Up Studies; Humans; Injections, Intralesional; Magnetic Resonance Imaging; Male; Mouth Floor; Mouth Neoplasms; Neck Dissection; Picibanil; Postoperative Complications; Ranula; Suction; Treatment Outcome

The streptococcal antitumor agent OK-432 is commonly used as an immunopotentiator for immunotherapy in various types of malignant tumors including oral cancer. It has been demonstrated that OK-432 elicits an antitumor effect by stimulating immunocompetent cells, thereby inducing multiple cytokines including interferon (IFN)-γ, interleukin (IL)-2 and IL-12. Serum concentrations of IFN-γ in patients with oral cancer were examined 24 h after administration of OK-432. Serum concentrations of IFN-γ in patients with advanced cancer were significantly lower than those in patients with early cancer. These results suggested that some soluble factors produced by cancer cells may inhibit IFN-γ production with OK-432. Thus, in the present study, an in vitro simulation model was established for the immune status of patients with oral cancer by adding conditioned medium (CM) derived from oral cancer cell lines into a culture of peripheral blood mononuclear cells (PBMCs) derived from a healthy volunteer. We investigated whether soluble factors derived from oral cancer cells affected IFN-γ production from PBMCs following stimulation with OK-432. PBMCs stimulated with OK-432 produced a large amount of IFN-γ; however, both IFN-γ production and cytotoxic activity from PBMCs induced by OK-432 were inhibited by the addition of CM in a dose-dependent manner. In order to examine these inhibitory effects against IFN-γ production, the contribution of inhibitory cytokines such as IL-4, IL-6, IL-10, transforming growth factor-β and vascular endothelial growth factor was investigated. However, neutralization of these inhibitory cytokines did not recover IFN-γ production inhibited by CM. These results indicated that unknown molecules may inhibit IFN-γ production from PBMCs following stimulation with OK-432.

Topics: Antineoplastic Agents; Biological Factors; Cell Line, Tumor; Culture Media, Conditioned; Humans; Interferon-gamma; Interleukins; Leukocytes, Mononuclear; Mouth Neoplasms; Picibanil; RNA, Messenger; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Cytokines; Dendritic Cells; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Leukocytes, Mononuclear; Male; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Picibanil; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Th1 Cells; Th2 Cells; Transcription Factors

A patient with malignant melanoma of the oral cavity who lived for a long period despite developing liver metastasis is presented. An 81-year-old female was referred to our hospital because of a pigmented tumor of the lower gingiva. Under the clinical diagnosis of malignant melanoma, she underwent bilateral functional neck dissection and marginal mandiblectomy. Histological diagnosis of the operation material was malignant melanoma with regional lymph node metastasis. In spite of loco-regional control, liver metastasis developed at 7 months after the surgery. She then underwent combination chemotherapies with dimethyl triazeno imidazole carboxamide (DTIC), nimustine hydrochloride (ACNU) and vincristin (DAV therapy), or cisplatin, DTIC, ACNU and tamoxifen (DAC-tam), but no marked response was obtained. Considering the advanced age of the patient, immunotherapy with a biological response modifier, OK432, alone was started. After administration of OK432, the metastatic tumor gradually decreased, and she is alive without any clinical symptoms of tumor at 46 months after the detection of liver metastasis, although it is still present on ultrasonic and CT examinations.

Topics: Aged, 80 and over; Antineoplastic Agents; Female; Humans; Liver Neoplasms; Lymphatic Metastasis; Melanoma; Mouth Neoplasms; Picibanil; Treatment Outcome

Many authors have reported that oral melanoma patients showed much worse prognosis than those with cutaneous melanoma. We investigated treatment method and prognosis of patients with oral malignant melanoma.. Twenty-one patients with oral melanoma treated at our hospital were investigated, with special reference to the influence of preoperative surgical procedures such as biopsy, incision, or tooth extraction on the prognosis.. All patients underwent surgery followed by immuno-chemotherapy with dimethyl triazeno imidazole carboxamide (DTIC), ninustine hydrochloride (ACNU), vincristine (VCR), and biologic response modifier OK-432. Local control was obtained in 20 of 21 patients. Lymph node metastasis appeared in 13 patients, but neck failure was not detected in any patients. Distant metastasis occurred in 9 patients in spite of loco-regional control. Five-year survival rate of 12 patients with no preoperative surgical procedure was 91.7%, while that of the 9 patients who had undergone surgical procedures before treatment was 25.9% (P < .05).. Oral melanoma patients can obtain a prognosis as good as that for cutaneous melanoma patients, when the above-mentioned therapy is used without any preoperative surgical procedures.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Contraindications; Dacarbazine; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Nimustine; Picibanil; Prognosis; Risk Factors; Tooth Extraction; Vincristine

We have investigated the relationship between gene expression of Bcl 2 and Bax and the therapeutic effect in oral cancer patients. A significant correlation between Bcl-2/Bax gene expression ratio in the peripheral blood mononuclear cells (PBMCs) from the patients, and the therapeutic effect of radiation therapy in combination with UFT and OK-432, as well as survival rate, was observed. In addition, the statistically significant correlation was also observed between Bcl-2/Bax ratio and IFN-gamma and NK activity induced with OK-432. These findings suggest that Bcl-2 and Bax gene expression in PBMCs may be useful as a prognostic factor in oral cancer patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; bcl-2-Associated X Protein; Gene Expression; Genes, bcl-2; Humans; Interferon-gamma; Killer Cells, Natural; Mouth Neoplasms; Picibanil; Survival Rate; Tegafur; Uracil

It is important to augment the anti-cancer host response in cancer treatment. Recent studies suggested that the signaling via Toll-like receptors (TLRs) which are newly identified receptor molecules recognizing many pathogens, are involved in the induction of anti-cancer immunity. Seya et al. demonstrated that maturation of dendritic cells (DCs) and cytokine induction by the cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin (BCG-CWS) are induced via both TLR2 and TLR4. Akira et al. discovered a new molecule of TLR family, TLR9, recognizing unmethylated bacterial CpG-DNA, whose clinical use is expected for cancer therapy as a potent inducer of a helper T cell 1 (Th1)-type T-cell response. TLR9-deficient mice did not show any responses to CpG-DNA, including Th 1 cytokine production and maturation of DCs. We have obtained two molecules, a lipoteichoic acid-related molecule isolated from streptococcal agent OK-432, and a plant-derived 55-kDa protein that can induce Th1 response and elicit a strong anti-cancer effect in vivo and in vitro. Our basic experiments demonstrate that TLR4 signaling is intimately involved in anti-cancer immunity induced by these immunopotentiators. Our clinical examination in oral cancer patients also suggests the requirement of both TLR4 and MD-2 in the OK-432-induced anti-cancer host response. Establishment and clinical use of the methodology for human cancer therapy by utilizing TLR signaling is greatly expected.

Topics: Adjuvants, Immunologic; Animals; Antigens, Surface; CpG Islands; Cytokines; Dendritic Cells; DNA-Binding Proteins; Drosophila Proteins; Humans; Interferon-gamma; Lymphocyte Antigen 96; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; Models, Immunological; Mouth Neoplasms; Mycobacterium bovis; Neoplasms; Neoplasms, Experimental; Picibanil; Receptors, Cell Surface; Th1 Cells; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 6; Toll-Like Receptor 9; Toll-Like Receptors

A well-known metastic model of human oral cancer employs 9,10-dimethyl-1,2-benzanthracene (DMBA) to induce hamster cheek-pouch carcinoma. Streptococcal immunopotentiator OK432 was studied here for its inhibitory effect on lymph-node metastasis in that model. The intraperitoneal administration of OK432, after excision of cheek-pouch tumours induced by DMBA, resulted in a marked reduction in the incidence of cervical lymph-node metastasis to 7%, a significant decrease beneath the rates observed for control animals not receiving OK432 (40%). OK432 also caused an increased in serum levels of tumour necrosis factor-alpha and interleukin-6 in tumor-bearing hamsters. These results suggest that the immune response may play an important part in the antimetastatic effects of OK432.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adjuvants, Immunologic; Animals; Antineoplastic Agents; Carcinogens; Carcinoma, Squamous Cell; Cheek; Cricetinae; Disease Models, Animal; Humans; Injections, Intraperitoneal; Interleukin-6; Lymphatic Metastasis; Male; Mesocricetus; Mouth Neoplasms; Picibanil; Tumor Necrosis Factor-alpha

The influence of OK-432, a streptococcal preparation, on human polymorphonuclear leukocytes (PMN) was examined. OK-432 increased O2- generation was also observed when PMN were cultured with 10(-2)KE/ml OK-432 for 1 h and then stimulated with phorbol myristate acetate or formyl-metionyl-leucil-phenylalanine (FMLP). In addition, PMN O2- generation was promoted by culture supernatants of peripheral blood mononuclear cells (PBMC) incubated with 10(-3) or 10(-2) KE/ml OK-432. Furthermore, OK-432 (10(-3)-10(-2) KE/ml) enhanced the chemiluminescence of FMLP- and PMA-stimulated PMN. However, nitroblue tetrazolium reduction and myeloperoxidase activity were only minimally enhanced. Not only the candidacidal activity of PMN but also antibody-dependent cell-mediated cytotoxicity against Candida and Raji cells were enhanced in correspondence with the increased generation of reactive oxygen species. Culture of PMN or PBMC for 24 h with OK-432 resulted in a concentration-dependent increase in the substantial production of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha. OK-432 also enhanced granulocyte-macrophage colony stimulating factor and gamma-interferon generation by leukocytes in a dose-dependent manner. Our research indicates that OK-432 enhances PMN function directly as well as via the promotion of cytokine production, and suggests that these effects of OK-432 could be beneficial in immunosuppressed patients.

Topics: Candida albicans; Carcinoma, Squamous Cell; Combined Modality Therapy; Cytokines; Cytotoxicity, Immunologic; Humans; In Vitro Techniques; Leukocytes, Mononuclear; Luminescent Measurements; Mouth Neoplasms; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Nitroblue Tetrazolium; Phagocytosis; Picibanil; Superoxides; Tetradecanoylphorbol Acetate

A streptococcal preparation, Sapylin, was employed for 27 cases of oral squamous cancer without treatment that was injected into normal submucosa or sub-skin around the tumor. The recent clinical efficacy is as follows: 3 cases specially effective, 10 cases marked effective, 6 cases effective and 8 cases not effective. Effective percent 70%. A delayed SK-SD skin reaction were found to enhance, but NK activity and T-Rosette were not. A middle grade fever was present as a side effect of this preparation. The result suggested Sapylin that may be a useful to biological response modifier (BRM) agent for oral squamous cancer.

Topics: Biological Products; Carcinoma, Squamous Cell; Female; Humans; Immunologic Factors; Immunotherapy, Active; Injections, Subcutaneous; Male; Middle Aged; Mouth Neoplasms; Picibanil

A secondary metastasis after surgery was uncovered in 12 out of 73 cases of oral squamous cancer. The clinical and histological characteristic tendencies of the metastasis of these 12 cases were the tongue as the tumor site (11/12), and an aggressive invasion in the tumor-host borderline with 2 of Gr, 3, 5 of Gr. 4C and 5 of Gr. 4D, according to the grading of Yamamoto and Kohama (1982). The control of these metastases was not easy because of their multiple and extra-nodal spread. Tumor-free survival occurred in 4 out of 11 (36.3%). Therefore, in some situations, a prophylactic neck dissection would seem to be recommended.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Mouth; Mouth Neoplasms; Neck Dissection; Neoplasm Invasiveness; Picibanil; Postoperative Period; Tongue Neoplasms

The influence of preoperative perilesional therapy with the potent bacterial biological response modifier (BRM) OK-432 on natural killer (NK) cell activity in peripheral blood and tumor draining lymph nodes (LNs) of patients with head and neck cancer (HNC) has been investigated. Pretreatment NK activity in peripheral blood (PB) was comparable within the group of HNC patients. However, after perilesional OK-432 therapy, a significant increase in cytotoxicity was observed by day 8. Furthermore, postoperative suppression of PB NK activity was less pronounced in patients with OK-432 therapy. In tumor draining LNs, NK activity was significantly higher in patients receiving OK-432 therapy than in those treated by surgery alone. No differences were detected concerning the in vitro stimulatory capacity of interferon (IFN) and/or Staphylococcus protein A (SPA) on LN NK activity in both the OK-432 treated and untreated group. Furthermore, by immunoperoxidase technique, LNs of OK-432 treated patients were found to express a higher number of cells reacting with the monoclonal antibody HNK-1 compared to LNs of the untreated group. Both these results suggest that perilesional OK-432 therapy leads to an increase in number and function of NK cells in regional LNs, together with an increase in NK activity in PB in some but not all patients.

Topics: Adult; Aged; Biological Products; Female; Humans; Immunosuppression Therapy; Immunotherapy; Killer Cells, Natural; Lymph Nodes; Male; Middle Aged; Mouth Neoplasms; Picibanil

Although the drug OK-432 can induce the release of gamma-interferon (IFN-gamma), the serum concentrations of IFN-gamma produced are very low. We studied the effects of combining OK-432 with alpha-interferon (IFN-alpha) on the endogenous production of IFN and the postoperative courses of patients with oral cavity cancers. Forty patients operated on for head and neck cancers were studied. Each patient was given an injection of OK-432 1 week after surgery. Between 10 and 14 days later, a combination of OK-432 and IFN-alpha was given to assess the effects of the concomitant use of IFN-alpha on IFN production. In 18 of the 30 patients given a large dose of IFN-alpha (3 or 5 X 10(6) IU/mg protein), IFN production induced by OK-432 was enhanced. A small dose of IFN-alpha (7 X 10(3) IU) did not enhance the action of OK-432. OK-432 also induced the release of both endogenous IFN-gamma and IFN-alpha, and the production of both types of IFN was enhanced by the concomitant administration of parenteral IFN-alpha. Next, 50 patients operated on for oral cavity cancers were given OK-432 or a combination of OK-432 and IFN-alpha for 4 months, and their postoperative courses were followed for 2-5 years. The clinical courses were better in the combined therapy group than in the group given OK-432 alone.

Topics: Biological Products; Combined Modality Therapy; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Interferon Type I; Interferon-gamma; Mouth Neoplasms; Picibanil

The streptococcal preparation OK-432 was used by intradermal administration as an immunotherapy in 18 patients with oral cancer, and the sera from patients during OK-432 treatment were serially assayed for interferon (IFN) activity by the plaque-reduction method with vesicular stomatitis virus in FL cells derived from human amniotic membrane. The type of serum IFN was characterized by acid-treatment and neutralization test with anti-IFN-alpha and anti-IFN-beta antisera. IFN-gamma was expressed for its titer as the residual IFN activity after neutralization with both antisera. An intradermal injection of OK-432 transiently induced IFN activity and 3 patterns in the type and level of the produced IFN were observed. Although most of the patients induced IFN-gamma and acid-stable IFN or only IFN-gamma, 2 patients seemed to be unresponsive to OK-432. When we examined the relationship between natural killer (NK) activity and IFN titer, a sharply declined NK activity was found immediately post OK-432 administration, and then NK activity stayed around the pretreatment level. Most of the tested patients' induced IFN-gamma, preceding the step toward the gradual increase in NK activity, decreased with OK-432. However, even in the patients showing no IFN induction with OK-432, a significant decrease of NK activity occurred.

Topics: Aged; Biological Products; Carcinoma, Squamous Cell; Female; Humans; Immunotherapy; Injections, Intradermal; Interferons; Killer Cells, Natural; Male; Middle Aged; Mouth Neoplasms; Picibanil; Vesicular stomatitis Indiana virus

Topics: Adult; Aged; Female; Head and Neck Neoplasms; Humans; Hypersensitivity, Delayed; Laryngeal Neoplasms; Male; Middle Aged; Mouth Neoplasms; Nose Neoplasms; Picibanil; Prognosis; Skin Tests; T-Lymphocytes

Topics: Biological Products; Breast Neoplasms; Esophageal Neoplasms; Female; Humans; Lung Neoplasms; Male; Mouth Neoplasms; Neoplasms; Pharyngeal Neoplasms; Picibanil; Radiotherapy Dosage